Enantioselective alkylations of tributyltin enolates catalyzed by Cr(salen)CI: Access to enantiomerically enriched all-carbon quaternary centers

Article abstract of DOI:10.1021/ja043601p

The catalytic asymmetric α-alkylation of tributyltin enolates with a range of primary alkyl halides is catalyzed by a chiral Cr(salen) complex. The reaction constitutes the first transition-metal-catalyzed system for α-alkylation of carbonyl substrates wi

Full text of DOI:10.1021/ja043601p

Published on Web 12/08/2004
Enantioselective Alkylations of Tributyltin Enolates Catalyzed by Cr(salen)Cl:
Access to Enantiomerically Enriched All-Carbon Quaternary Centers
Abigail G. Doyle and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received October 21, 2004; E-mail: jacobsen@chemistry.harvard.edu
Table 1. Preliminary Screen of Tributyltin Enolate Alkylationa
R-Alkylations of carbonyl compounds are indispensable C-C
bond-forming reactions in synthetic organic chemistry.1 Asymmetric
variants rely predominantly upon the use of chiral auxiliaries, which
often provide exceptional levels of selectivity.2 For both practical
and fundamental reasons, broadly applicable catalytic asymmetric
alkylation reactions of enolates have been a long-sought goal.
Whereas highly efficient transition-metal-catalyzed asymmetric
R-allylations,3 arylations,4 and vinylations5 of ketones have been
identified, relatively limited progress has been made in catalytic
alkylations with sp3-hybridized electrophiles. Three distinct strate-
gies for catalytic alkylation with alkyl halides have been reported,
each involving organic molecules as catalysts.6-8 In most cases,
these systems enable preparation of carbonyl products bearing
R-tertiary stereocenters. Access to enantioenriched carbonyl prod-
ucts bearing R-quaternary centers by catalytic means remains largely
an unsolved, albeit highly important, problem.9,10 Herein, we report
the catalytic asymmetric R-alkylation of tributyltin enolates with a
range of commonly used electrophiles catalyzed by a chiral
Cr(salen) complex. Alkylations of tetrasubstituted tin enolates of
five-, six-, and seven-membered ring ketones proceed with high
enantioselectivity and in synthetically useful yields to afford
alkylation products bearing quaternary stereocenters.
On the basis of promising activity displayed by salen metal
complexes in catalytic epoxide addition and iodoetherification
reactions, we explored the possible utility of these catalysts in
enolate alkylation reactions.11,12 Initial screens revealed that among
various enolates of cyclohexanone, tributyltin derivative 2 was
uniquely reactive for alkylation with methyl iodide promoted by
M(salen) complexes 1a-e (Table 1).13,14 Whereas Ti (1b), Al (1c),
and Mn (1d) complexes all provided R-alkylation product 3 in low
enantioselectivity, chromium complex 1e catalyzed the alkylation
in a more promising 30% ee, albeit in low yield. Efforts to optimize
this result led to the following observations.14 (1) Steric and
electronic variations of the salen ligand framework influenced both
the reactivity and the enantioselectivity of the chromium catalyst,
with complexes bearing electron-withdrawing ligand substituents
proving completely unreactive. Best results were obtained with
complex 1e. (2) The reaction enantioselectivity was solvent-
dependent, with aromatic solvents, such as benzene and chloroben-
zene, affording best results. (3) Decreasing the reaction temperature
led to marked increases in enantioselectivity (entries 6-9). At
temperatures below 4 °C, however, product yield was significantly
depressed even at prolonged reaction times.
entry
catalyst
M
solvent
temp (°C)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1a
CoCl
TiCl2
AlCl
MnCl
CrCl
CrCl
CrCl
CrCl
CrCl
TBME
TBME
TBME
TBME
TBME
C6H6
C6H6
C6H5Cl
C6H5Cl
23
23
23
23
23
23
4
0
14
15
34
42
38
69
53
26
1bd
1c
14
5
4
30
49
60
58
84
1dd
1e
1e
1ed,e
1ed,e
1ed,e
4
-40
a Unless noted otherwise, reactions were carried out with 0.007 mmol
of catalyst 1, 0.07 mmol of tin enolate, and 0.28 mmol of methyl iodide in
500 µL of solvent. b Determined by GC analysis relative to 1-decene as
internal standard. c Determined by chiral GC analysis. d Reactions carried
out using 175 µL of solvent. e Reaction carried out using 20 mol % catalyst.
extend well to other electrophiles; reactions with benzyl bromide
and allyl bromide afforded alkylation products in modest yields
and enantioselectivities.15
Whereas trisubstituted enolate 2 was observed to undergo
decomposition during the course of the reaction, tetrasubstituted
enolate 4a proved to be significantly more robust as a reacting
partner. This nucleophile was more reactive and underwent alkyl-
ation with an enantioselectivity higher than that of 2 under the
reaction conditions outlined above with a broad range of common
electrophiles (Table 2). Furthermore, catalyst loadings as low as
2.5 mol % 1e could be used, and the reactions were complete within
2 h at 0 °C. In addition to five-membered ring substrate 4a, six-
and seven-membered ring tetrasubstituted enolates 4b-d underwent
alkylation in good yield and high enantiomeric excess. In all cases,
SN2 addition was observed exclusively, in preference to SN2′ or
carbonyl addition, and with minimal (<5%) generation of over-
alkylation products.16 Alkylation of tin enolates 4a and 4d with
propargyl bromide, for example, proceeded to form 5b and 5i as
the only detectable products in 96 and 92% ee, respectively. The
more hindered tin enolate 4c also proved to be a competent reacting
partner, affording products 5g and 5h in modest yield and good
enantiomeric excess.17
Despite the encouraging enantioselectivity obtained in these
exploratory studies, the yields of alkylation product were generally
low. Best yields (69%) were obtained at elevated catalyst loading
(20 mol % 1e) and increased reaction concentration, but further
efforts directed toward optimization of this system with this
substrate combination proved unfruitful. Moreover, the specific
conditions developed for alkylation with methyl iodide did not
The sense of absolute stereoinduction in the alkylation reactions
was reversed for products 5e, 5g, and 5h relative to the other
9
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J. AM. CHEM. SOC. 2005, 127, 62-63
10.1021/ja043601p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Alkylation of Tetrasubstituted Tin
stereocenters. To our knowledge, it also represents the only
transition-metal-catalyzed system for R-alkylation of carbonyl
substrates with alkyl halides. The synthetic and mechanistic
implications of this discovery are the focus of our ongoing efforts.
Enolatesa
Acknowledgment. This work was supported by the NIH (GM
43214) and by a predoctoral fellowship from the Department of
Defense to A.G.D.
Supporting Information Available: Representative experimental
procedures, characterization data, and chiral chromatographic analyses
of racemic and enantiomerically enriched products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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a Reactions were carried out on a 0.5 mmol scale with external
temperature control (ice bath). b Isolated yield after silica gel chromatog-
raphy. c Determined by chiral GC analysis unless noted otherwise. d De-
termined by chiral HPLC analysis. e Reaction carried out using 2.5 mol %
catalyst. f Reaction carried out using 5.0 mol % catalyst. g Reaction carried
out using 10 mol % catalyst.
15749.
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(14) See Supporting Information for details.
(15) For example, in chlorobenzene at -40 °C, 2-benzyl cyclohexanone was
obtained in 83% yield and 53% ee, and 2-allyl cyclohexanone was obtained
in 60% yield and 46% ee.
products,14 a rather striking result given the uniformly high
enantioselectivities obtained in each case. Possible mechanisms
involving enolate activation (via Sn or Cr ate complexes) and/or
alkyl halide activation by the chiral Cr complex are being evaluated
in the context of this intriguing stereochemical phenomenon.
This method provides efficient and highly selective access to
enantioenriched R-carbonyl all-carbon-substituted quaternary
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(17) Product 5h could not be accessed by the alternative approach involving
alkylation of 4b with ethyl iodide.
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